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PubMed1989

Robust methods for the detection of genetic linkage for quantitative data from pedigrees.

The robust method for detecting linkage developed by Haseman and Elston [The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2:3-19, 1972] for data from sib pairs is extended to any type of noninbred relative pair. The regression of the squared relative-pair trait difference on the estimated proportion of genes identical by descent (i.b.d.) at a marker locus is shown to depend upon the recombination fraction between the two loci; the regression coefficient is negative if the trait and marker loci are linked. A test for linkage based on data from any informative type of relative pair can thus be obtained by testing that this regression coefficient is less than zero. Formulae for the asymptotic power of such tests for linkage based upon independent relative pairs are developed. Results are also given for the special case in which the proportion of genes shared i.b.d. for relative pairs is known. Finally, a general algorithm is described that will incorporate all available pedigree data to calculate an estimate of the proportion of genes that a relative pair shares i.b.d. at a marker locus.

Genetic Linkage↗
PubMed1995

Use of robust statistical methods to determine the effect of fragile X on means and variance components of a quantitative trait.

Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance.

Adolescent↗
PubMed2006

Validity, efficiency, and robustness of a family-based test of association.

We propose a new test of linkage in the presence of allelic association that uses all available information in a sample of nuclear families, including parental phenotypes, genotypes from both affected and unaffected siblings, and families with homozygous parents. The test is based on the conditional framework developed by Rabinowitz and Laird [2000: Hum Hered 50:211-223] and is thus immune to population stratification and can be applied to families with any pattern of missing information. The test statistic is a conditional likelihood ratio based on a standard two-point linkage model with allelic association, where parameters are estimated from the sample. Through a simulation study, we determined that the proposed test has near optimal power for a wide range of scenarios, outperforming FBAT both when data were complete and when parental genotypes were missing, although differences between the two tests diminish as the genetic effect is reduced. To assess robustness, we also evaluated the performance of the tests under scenarios with population stratification and found that although there is a loss of efficiency, our proposed test remains a strong competitor to FBAT.

Alleles↗
PubMed2002

Fast robust automated brain extraction.

An automated method for segmenting magnetic resonance head images into brain and non-brain has been developed. It is very robust and accurate and has been tested on thousands of data sets from a wide variety of scanners and taken with a wide variety of MR sequences. The method, Brain Extraction Tool (BET), uses a deformable model that evolves to fit the brain's surface by the application of a set of locally adaptive model forces. The method is very fast and requires no preregistration or other pre-processing before being applied. We describe the new method and give examples of results and the results of extensive quantitative testing against "gold-standard" hand segmentations, and two other popular automated methods.

Algorithms↗
PubMed2005

Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by Robust Dosage PCR (RD-PCR).

Fifty to eighty percent of Rett syndrome (RTT) cases have point mutations in the gene encoding methyl-CpG-binding protein-2 (MECP2). A fraction of MECP2 negative classical RTT patients has large heterozygous deletions. Robust Dosage PCR (RD-PCR) assays were developed as a rapid, convenient and accurate method to detect large heterozygous deletions and duplications. A blinded analysis was performed for 65 RTT cases from Portugal by RD-PCR in the coding exons 2-4 of the MECP2 gene. Neither the patients with point mutations nor the non-classical RTT patients without point mutation had a deletion or duplication. One of remaining eight female patients with classical RTT without point mutation had a heterozygous deletion. This is the first report of a deletion spanning the entire MECP2 gene. The deletion was confirmed by Southern blotting analysis and the deletion junction was localized 37 kb upstream from exon 1 and 18 kb downstream from exon 4. No duplications were detected. Our results suggest that RD-PCR is an accurate and convenient molecular diagnostic method.

Blotting, Southern↗
PubMed1988

Image registration in electron microscopy: application of a robust method.

The geometric registration of two electron microscopic images generally is performed by maximizing the cross-correlation coefficient between them. We show that a new similarity measure (the number of sign changes) is useful for performing simultaneously geometric and gray-level registration. This method is robust, which means that it provides a good estimation of the parameters even in the presence of outliers that cannot be described by the registration model.

Computer Simulation↗
PubMedDate not supplied

Correspondence of closest gradient voxels--a robust registration algorithm.

A robust, automatic volume registration algorithm based on intensity gradients is presented. This algorithm can successfully perform registrations under conditions of unrelated intervolume voxel intensities, significant object displacements, and/or significant amounts of missing data. It also allows the user to visualize the registration convergence, clearly illustrating any source of registration errors. This algorithm consists of a matching algorithm based on iteratively finding the correspondence of the closest voxels containing a high three-dimensional intensity gradient magnitude. This algorithm was tested by registering T2-weighted MR volumes that had undergone varying displacement transformations to simultaneously acquired proton-density volumes. These transformations involved rotations of up to 25 degrees followed by translations of up to 25 mm along the axis of rotation. For all registrations, the mean registration error was less than one-fifth of a voxel and the mean registration time was less than 30 minutes. In conclusion, this algorithm is shown to be a powerful method of sequence-independent MR volume registration that is simple to both use and understand.

Algorithms↗
PubMed2006

In-line measurement of a drug substance via near infrared spectroscopy to ensure a robust crystallization process.

The crystallization of Etoricoxib, a polymorphic compound, has been optimized and controlled by seeding with the desired polymorph at a moderate supersaturation condition. To enhance the process robustness, near infrared spectroscopy (NIRS) has been evaluated as an inline measurement method for the concentration of Etoricoxib prior to seeding in the crystallization process. In this NIRS method, a spectral discriminant analysis based on principal component analysis (PCA) was established to detect the presence of solids produced by premature crystallization, or bubbles in the path of light. Once a spectrum was qualified as that of clear solution, concentration of Etoricoxib was calculated by a NIRS calibration model built with partial least squares (PLS) regression and with offline HPLC analysis as the reference method. This model was accurate with a standard error of cross validation (SECV) less than 1.2 mg/g Etoricoxib and a standard error of prediction (SEP) less than 1.7 mg/g over the concentration range from 50 to 170 mg/g, temperature range from 49 to 65 degrees C, and different sources of materials. In addition, all aspects of the offline HPLC method, especially the sampling procedure, were optimized to provide an accurate reference for NIRS calibration models. The application of this method at a pilot plant has demonstrated its capability of accurately measuring the process concentration of Etoricoxib as well as detecting the presence of solids produced by premature crystallization before seeding.

Calibration↗
PubMed2006

Sensitive capillary GC-MS-SIM determination of selective serotonin reuptake inhibitors: reliability evaluation by validation and robustness study.

A simple, fast, selective and very sensitive capillary GC-MS method for the simultaneous determination of five antidepressant drugs is described. Fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine belong to the newest and most important drug group termed selective serotonin reuptake inhibitors. Imipramine was used in this method as an internal standard for quantification. Optimum parameters for GC separation were investigated, i.e., flow rate, column head pressure, injector temperature, injection splitless conditions and oven temperature program. MS detection was performed in SIM mode to increase the sensitivity. Stability of the solutions, linear concentration range, accuracy, precision, LOD, LOQ (3.6-41.5 mg/L) and specificity were examined in the presence of excipients for checking the reliability of this method. The robustness was evaluated with a matrix of 15 experiments (seven factors and three levels) using Plackett-Burman fractional factorial experimental design, and Youden and Steiner statistical treatment. The method was applied to the analysis of these antidepressants in nearly all their pharmaceutical formulations, obtaining recoveries between 98.1% and 102.7% with regard to the claimed values.

Chemistry, Pharmaceutical↗
PubMed2005

An evaluation of the robustness of the Tanaka characterization protocol for reversed-phase liquid chromatography columns.

The robustness of the popular 'Tanaka' LC column characterization protocol has been evaluated by the statistical tools of reduced factorial design, multiple linear regression and principal component analysis. These have shown that in order to obtain reliable and reproducible results, it is especially important to control the methanol content, the temperature and, in the case of the total ion-exchange capacity test (alphaB/P pH 7.6), the pH of the mobile phase. In particular, the hydrophobicity tests (kPB and alphaCH2) are sensitive to small changes in methanol content. Provided that the operating parameters for the Tanaka column characterization protocol are controlled within the following experimental limits, i.e. methanol content +/-0.5% v/v, temperature +/-3degreesC, pH +/-0.10 and buffer concentration +/-2.0 mM, it is feasible to distinguish between RP materials that possess selectivity differences larger than their batch-to-batch reproducibility. These experimental requirements can be easily met by current LC instrumentation. Hence, the validity of the Tanaka testing protocol for characterizing columns has been verified.

Benzene Derivatives↗
PubMed2004

Robust automated shimming technique using arbitrary mapping acquisition parameters (RASTAMAP).

Quantitative MRI techniques as well as methods such as blood oxygen level-dependent (BOLD) imaging and in vivo spectroscopy require stringent optimization of magnetic field homogeneity, particularly when using high main magnetic fields. Automated shimming approaches require a method of measuring the main magnetic field, B(0), followed by adjusting the currents in resistive shim coils to maximize homogeneity. A robust automated shimming technique using arbitrary mapping acquisition parameters (RASTAMAP) using a 3D multiecho gradient echo sequence that measures B(0) with high precision was developed. Inherent compensation and postprocessing methods enable removal of artifacts due to hardware timing errors, gradient propagation delays, gradient amplifier asymmetry, and eddy currents. This allows field maps to be generated for any field of view, bandwidth, resolution, or acquisition orientation without custom tuning of sequence parameters. Field maps of an aqueous phantom show +/- 1 Hz variation with altered acquisition orientations and bandwidths. Subsequent fitting of measured shim coil field maps allows calculation of shim currents to produce optimum field homogeneity.

Echo-Planar Imaging↗
PubMed2004

Breath-hold water and fat imaging using a dual-echo two-point Dixon technique with an efficient and robust phase-correction algorithm.

A two-point Dixon technique using a novel phase-correction algorithm and commercially available dual-echo fast gradient-echo pulse sequence is presented. The phase-correction algorithm determines the directional rather than phase distribution of signals due to field inhomogeneities. Specifically, a region-growing scheme uses precalculated spatial gradients of the signal phase to guide the growth sequence, so there is no need to manually select the seeds or use an empirical angular threshold. Further, the determination of the signal direction of a given pixel is based on both the amplitude and phase of the surrounding pixels, the direction of which has already been determined. The advantages of this algorithm include its easy implementation, computational efficiency, and robustness in the presence of pixels with large phase uncertainty. The feasibility and usefulness of the technique are demonstrated in vivo with artifact-free water and fat images of an entire abdomen in a single breath-hold.

Abdomen↗
PubMed2006

Fast low-angle dual spin-echo (FLADE): a new robust pulse sequence for structural imaging of trabecular bone.

Mechanical strength and fracture resistance of trabecular bone (TB) are largely determined by the structural arrangement of individual trabeculae. Fast 3D spin-echo approaches are preferable to gradient echoes in that they are less sensitive to local induced gradients at the bone/marrow interface caused by magnetic susceptibility difference between the two tissues. FLASE is a 3D pulse sequence that serves this purpose. Here, we present a new pulse sequence dubbed FLADE (fast low-angle dual spin-echo) that overcomes some of the limitations inherent to FLASE, such as sensitivity to artifactual stimulated echoes. The double-echo sequence features a flip angle <90 degrees allowing for TR << T(1). The second phase-reversal pulse has the dual function of creating a second echo and restoring inverted longitudinal magnetization. The prolonged TR, made possible by sampling only half of k(z)-space, is used to collect navigator echoes in adjacent slabs for sensing subpixel translational displacements. FLADE is shown to provide SNR comparable to FLASE while having narrower point-spread function and being more robust to imperfections in the nonselective 180 degree pulses. Structural parameters derived from the in vivo images with the two pulse sequences are highly correlated, therefore suggesting that clinical data obtained with either pulse sequence can be merged.

Bone and Bones↗
PubMed2004

ICIQ: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence.

AIMS: To develop and evaluate the International Consultation on Incontinence Questionnaire (ICIQ), a new questionnaire to assess urinary incontinence and its impact on quality of life (QoL). METHODS: A developmental version of the questionnaire was produced following systematic literature review and views of an expert committee and patients. Several studies were undertaken to evaluate the psychometric properties of the questionnaire, including content, construct and convergent validity, reliability and sensitivity to change. RESULTS: The ICIQ was easily completed, with low levels of missing data (mean 1.6%). It was able to discriminate among different groups of individuals, indicating good construct validity. Convergent validity was acceptable, with most items demonstrating 'moderate' to 'strong' agreement with other questionnaires. Reliability was good, with 'moderate' to 'very good' stability in test-retest analysis and a Cronbach's alpha of 0.95. Items identified statistically significant reductions in symptoms from baseline following surgical and conservative treatment. Item reduction techniques were used to determine the final version and scoring scheme, which also demonstrated good psychometric properties. CONCLUSIONS: The final ICIQ comprises three scored items and an unscored self-diagnostic item. It allows the assessment of the prevalence, frequency, and perceived cause of urinary incontinence, and its impact on everyday life. The ICIQ is a brief and robust questionnaire that will be of use in outcomes and epidemiological research as well as routine clinical practice.

Adult↗
PubMed2005

A robust, streamlined, and reproducible method for proteomic analysis of serum by delipidation, albumin and IgG depletion, and two-dimensional gel electrophoresis.

Serum is a readily available source for diagnostic assays, but the identification of disease-specific serum biomarkers has been impeded by the dominance of human serum albumin and immunoglobulins (Igs) in the serum proteome. There is a need to reduce the technical variation in serum processing and analysis to allow for a reproducible analysis of large cohorts. To this end, we have developed a rapid and reproducible procedure for sample preparation and high-resolution two-dimensional gel electrophoresis to analyze human serum. Serum is centrifuged at high speed to remove lipids and aggregated proteins, incubated with protein G resin to remove IgG, precipitated with NaCl/ethanol to deplete albumin, and slowly resolubilized in a sodium dodecyl sulfate (SDS)/N-(2-hydroxyethyl)piperazine-2'-(2-ethanesulfonic acid) (HEPES) buffer. The delipidated and IgG/albumin depleted serum proteins are focused on pH 4-7 linear large immobilized pH gradient strips, and then resolved by Bis-Tris SDS-polyacrylamide gel electrophoresis. The robustness and reproducibility of the optimized procedure was determined for three individual serum samples on three consecutive days. An image analysis of the nine silver-stained gels demonstrated that the intensity and localization of protein spots are highly reproducible. Our IgG and albumin depletion procedure will aid in screening the patient sera for normal biological variation and disease-specific biomarkers.

Blood Proteins↗
PubMed2006

A robust meta-classification strategy for cancer detection from MS data.

We propose a novel method for phenotype identification involving a stringent noise analysis and filtering procedure followed by combining the results of several machine learning tools to produce a robust predictor. We illustrate our method on SELDI-TOF MS prostate cancer data (http://home.ccr.cancer.gov/ncifdaproteomics/ppatterns.asp). Our method identified 11 proteomic biomarkers and gave significantly improved predictions over previous analyses with these data. We were able to distinguish cancer from non-cancer cases with a sensitivity of 90.31% and a specificity of 98.81%. The proposed method can be generalized to multi-phenotype prediction and other types of data (e.g., microarray data).

Biomarkers, Tumor↗
PubMed2006

Robust protein quantitation in chromatographic fractions using MALDI-MS of tryptic peptides.

A method is introduced to evaluate protein concentrations using the height sum of all MALDI-MS peaks that unambiguously match theoretic tryptic peptide masses of the protein sought after. The method uses native chromatographic protein fractionation prior to digestion but does not require any depletion, labeling, derivatization, or preparation of a compound similar to the analyte. All peak heights of tryptic peptides are normalized with the peak height of a unique standard peptide added to the MALDI-MS samples. The sum of normalized peak heights, S(n), or the normalized mean peak height, M(n), reflects the concentration of the respective protein. For fractions containing various proteins, S(n) and M(n) can be used to compare concentrations of a protein between different fractions. For fractions with one predominating protein, they can be used to estimate concentration ratios between fractions, or to quantify the fractional protein concentration after calibration with pure protein solutions. Initial native fractionation retains the possibility to apply all conventional analytic procedures. Moreover, it renders the method relatively robust to MS mass accuracy. The method was validated with albumin, transferrin, alpha1-antitrypsin, and immunoglobulin G within highly complex chromatographic fractions of pathological and normal sera, which contained the respective intact native protein in dominating as well as minor concentrations. The correlation found between S(n) and the protein concentration as determined with ELISA showed that the method can be applied to select markers for distinguishing between normal and pathological serum samples.

Blood Proteins↗
PubMed2002

A robust micro-electrospray ionization technique for high-throughput liquid chromatography/mass spectrometry proteomics using a sanded metal needle as an emitter.

A 60 microm internal diameter (i.d.) stainless-steel needle was adapted to the orthogonal ESI probe ( microESI) of a commercial ion trap mass spectrometer, and used for capillary liquid chromatography/tandem mass spectrometry (LC/MS/MS) protein identification experiments. The modification allows for the use of nitrogen sheath gas which helps in the nebulization at LC flow rates exceeding 500 nL/min and eliminates problems caused by liquid junctions commonly used to initiate nanospray ionization (NSI). A comparison is made between the performance of a 75 microm i.d. column with a 15 microm pulled glass tip using a liquid junction, and that of a 150 microm i.d. column using the new microESI device. The combination of the 150 microm i.d. column and microESI gave sensitivity close to that of NSI (250 attomoles horse heart myoglobin digest on column), and proved to be more robust than the standard pulled glass tips of similar i.d. No evidence of metal needle catalyzed oxidation of methionine was observed during analysis of the tetrapeptide MRFA under a range of test conditions. Phosphorylated peptides in a beta-casein tryptic digest were also successfully identified using the microESI interface with a steel needle. In addition it was found that a mild sanding of the metal needle tip improved spray performance.

Animals↗